Technical Field
[0001] The present invention relates a novel radioactive fluorine-labeling precursor compound
and a production method of a radioactive fluorine-labeled compound using the precursor
compound.
Background Art
[0002] Conventionally, a radioactive fluorine-labeling reaction is often performed by preparing
a labeling precursor compound which is a compound having a leaving group bonded to
a site to be fluorine-labeled of a target substrate and performing a nucleophilic
substitution reaction in which radioactive fluoride ion F is allowed to react with
the labeling precursor compound. In general, this reaction is performed by using a
small amount of radioactive fluoride ion F with respect to a large amount of labeling
precursor compound. Therefore, purification of the obtained radioactive fluorine-labeled
compound is usually performed by separating a large amount of unreacted labeling precursor
compound by a high-performance liquid chromatography (HPLC) method.
[0003] However, the HPLC method is cumbersome and takes time, and thus causes degradation
of yield of the object compound in consideration of the half-life of radioactive fluorine
of 110 minutes. As an alternative strategy requiring no HPLC purification, Patent
Literatures 1 and 2 have proposed that a labeled compound is made easy to separate
from another species without a compound M (purification site) by modifying a part
of a leaving group of the labeling precursor compound with a compound M (purification
site), and this compound is allowed to be used as a labeling precursor compound and
to react with a nucleophilic agent such as radioactive fluoride ion F.
[0004] In addition, the present applicant has already filed a patent application for a labeling
precursor compound and a labeling method using a novel leaving group different from
the conventional leaving group (Patent Literature 3).
Citation List
Patent Literature
Summary of Invention
[0006] The method described in Patent Literature 1 is based on the concept that an active
group immobilized on a resin chemically acts on the purification site M of the precursor
compound after the radioactive fluorination reaction. Therefore, there has been a
problem in that radioactive fluorination rate is adversely affected, preparation of
resins such as those having a specific active group introduced thereinto is required,
or addition of further reaction conditions such as heating or addition of a reagent
after the radioactive fluorination reaction is required.
[0007] The method described in Patent Literature 2 is based on the concept that a difference
between logD of a labeling precursor compound and logD of a radioactive labeled compound
is 1.5 or more, such that separation of the radioactive labeled compound is easily
performed. However, there have been problems in that the type of leaving group disclosed
in Patent Literature 2 is limited, designing in accordance with the characteristics
of individual substrates is difficult, and poisonous chlorosulfonic acid needs to
be used in synthesis. In addition, further improvement of purity of the separated
radioactive labeled compound is required.
[0008] In addition, the method of Patent Literature 3 requires that the substrate is a compound
having a neopentyl group, but does not focus on any application to a compound having
no neopentyl group.
[0009] An object of the present invention is to provide a method which enables a leaving
group to be flexibly designed, maintains a radioactive fluorination rate at the same
degree as in conventional methods, and can separate and purify a radioactive fluorine-labeled
compound from an unreacted precursor compound by a simple purification method after
the radioactive fluorination reaction.
[0010] As a result of diligent research to solve the problems described above, the present
inventors have found that a method which can maintain a radioactive fluorination rate
at the same degree as in conventional methods and can separate and purify a radioactive
fluorine-labeled compound from an unreacted precursor compound by a simple purification
method after a radioactive fluorination reaction can be provided by introducing a
hydrophobic amide tag into a benzene ring of a leaving group formed of a benzenesulfonyloxy
group, thereby completing the present invention.
[0011] That is, according to an aspect of the present invention, there is provided a labeling
precursor compound for a radioactive fluorine-labeled compound represented by the
following general formula (1):
wherein S represents a substrate, and L represents a straight alkyl group having 1
to 6 carbon atoms, which may contain an ether group,
the labeling precursor compound being represented by the following general formula
(2):
wherein S and L are the same as in the general formula (1), R1 and R2 each independently represent a straight or branched alkyl group having 1 to 30 carbon
atoms, or a substituted or unsubstituted monocyclic or condensed polycyclic aryl group,
R3 each independently represent an alkyl group having 1 to 4 carbon atoms or an alkoxy
group having 1 to 4 carbon atoms, and
p represents an integer of 0 to 4.
[0012] In addition, according to another aspect of the present invention, there is provided
a production method of a radioactive fluorine-labeled compound, the method including
a step of allowing the aforementioned labeling precursor compound to react with [
18F]fluoride ion to obtain the radioactive fluorine-labeled compound represented by
the aforementioned general formula (1).
[0013] According to the present invention, since a compound represented by the general formula
(2), that is, a compound in which a hydrophobic amide substituent is introduced into
a benzene ring of a benzenesulfonyloxy group which is a leaving group, is used as
a labeling precursor compound for a radioactive fluorine-labeling reaction, a radioactive
fluorination rate is maintained at the same degree as in conventional methods, and
a radioactive fluorine-labeled compound can be separated and purified from an unreacted
precursor compound by a simple purification method after a radioactive fluorination
reaction.
Description of Embodiments
1. Radioactive fluorine-labeling precursor compound
[0014] A radioactive fluorine-labeling precursor compound of the present invention is a
precursor compound for a radioactive fluorine-labeled compound represented by the
general formula (1), and has a structure represented by the general formula (2). clogP
(clogP
(1)) of the radioactive fluorine-labeled compound represented by the general formula
(1) is preferably -1.4 to 5.0 and more preferably 2.0 to 5.0. The labeling precursor
compound is designed such that a difference (clogP
(2) - clogP
(1)) between clogP(clogP
(1)) of the radioactive fluorine-labeled compound represented by the general formula
(1) and clogP (clogP
(2)) of the precursor compound represented by the general formula (2) is preferably 2
or more, more preferably 3 or more, still more preferably 5 or more, and particularly
preferably 8 or more. The upper limit thereof is not particularly limited, but the
difference between clogPs (clogP
(2) - clogP
(1)) is preferably 50 or less and is more practically 30 or less in consideration of
solubility of the precursor compound in a reaction solution. By doing so, after the
radioactive fluorine-labeling reaction, the unreacted precursor compound and the targeted
radioactive fluorine-labeled compound can be easily separated from each other in a
short time by simple column chromatography such as a reverse-phase cartridge column.
[0015] In the present invention, the alkyl group of R
1 and R
2 includes a straight or branched alkyl group having 1 to 30 carbon atoms among which
the number of carbon atoms is preferably 4 to 24 and more preferably 8 to 18, and
a straight alkyl group is preferable. The monocyclic aryl group of R
1 and R
2 includes a phenyl group, and the condensed polycyclic aryl group of R
1 and R
2 include a naphthyl group, an anthracenyl group, and the like. In the alkyl group
and the monocyclic or condensed polycyclic aryl group, a hydrogen atom may be substituted
by an alkyl group, an alkoxy group, a halogen atom, or the like. R
1 and R
2 may be the same or different, but are preferably the same group. A group represented
by -CONR
1R
2 of the precursor compound of the present invention may be bonded to any of a meta-position,
an ortho-position, and a para-position of the phenyl group, but is preferably bonded
to a para-position of the phenyl group.
[0016] Note that, in the present specification, halogen means fluorine, chlorine, bromine,
or iodine.
[0017] In the present invention, an example of the alkyl group of R
3 includes a straight or branched alkyl group having 1 to 4 carbon atoms, and an example
of the alkoxy group of R
3 includes a straight or branched alkoxy group having 1 to 4 carbon atoms. In the precursor
compound of the present invention, p represents an integer of 0 to 4, among which
p is preferably 0 that is, a case where the phenyl group of the compound represented
by the general formula (2) is substituted by no other substituents than -CONR
1R
2.
[0018] The radioactive fluorine-labeling precursor compound of the present invention is
preferably one represented by the general formula (2) in which -CONR
1R
2 (R
1 and R
2 each independently preferably represent a straight alkyl group having 1 to 30 carbon
atoms, or a substituted or unsubstituted condensed polycyclic aryl group) is bonded
to a para-position, and p is 0.
[0019] In the present invention, L represents a straight alkyl group (linker) having 1 to
6 carbon atoms, which may contain an ether group. L can be, for example, a group represented
by *-O(CH
2)
n-, *-(CH
2)
n-, or *-(OCH
2CH
2)
m-wherein n is an integer of 1 to 5, m is an integer of 1 to 3, and * represents a
binding site to S.
[0020] In the present invention, S can be arbitrarily adopted as long as the compound represented
by the general formula (1) is one used as a radiopharmaceutical. However, S can be,
for example, a group represented by the following formula (S-1) or a group represented
by the following formula (S-2).
In the formula (S-1), S' is a part of S, q is 0 or 1, and the asterisk is a binding
site to L.
In formula (S-2), S' is a part of S, X
1 and X
3 each independently represent a hydrogen atom or a halogen atom, and X
2 represents a hydrogen atom, a halogen atom, or a nitrile group, but at least one
of X
1, X
2, and X
3 is a halogen atom, and the asterisk is a binding site to L.
[0021] In the present invention, specific examples of the group represented by the formula
(S-1) include groups represented by the following formulas (S-3), (S-4), (S-5), and
(S-6).
wherein q is the same as in the formula (S-1), R
11 is a halogen atom, and the asterisk represents a binding site to L.
wherein q is the same as in the formula (S-1), J is O, S, NH, or NMe, the asterisk
represents a binding site to L, and, here, Me represents a methyl group.
wherein q is the same as in the formula (S-1), Z is carbon or nitrogen, Me represents
a methyl group, and the asterisk represents a binding site to L.
wherein q is the same as in the formula (S-1), Pg
1 represents a protecting group of an amino group, Pg
2 represents a protecting group of a carboxyl group, and the asterisk is a binding
site to L.
[0022] In the formula (S-3), q is preferably 1. In addition, in a case where S is a group
represented by formula (S-3), L is preferably a group presented by *-O(CH
2)
n- wherein * is a binding site to the formula (S-3), and n is an integer of 1 to 5
and preferably 2 to 4.
[0023] In the formula (S-4), q is preferably 0, and J is preferably O. In addition, in
a case where S is a group represented by the formula (S-4), L is preferably a group
presented by *-O(CH
2)
n- wherein * is a binding site to the formula (S-4), and n is an integer of 1 to 5
and preferably 2.
[0024] In the formula (S-5), q is preferably 0. In addition, in a case where S is a group
represented by the formula (S-5), L is preferably a group presented by *-(OCH
2CH
2)
m- wherein * is a binding site to the formula (S-5), and m is an integer of 1 to 3
and preferably 3.
[0025] In the formula (S-6), q is preferably 0. In addition, in a case where S is a group
represented by the formula (S-6), L is preferably a group presented by *-(CH
2)
n- wherein * is a binding site to the formula (S-6), and n is an integer of 1 to 5
and preferably 2.
[0026] In addition, in the present invention, a specific example of the group represented
by the formula (S-2) includes a group represented by the following formula (S-7).
wherein X
1, X
2, and X
3 are the same as in the formula (S-2), R
12 represents a hydrogen atom, a halogen atom, or CO
2R
a, R
a represents an alkyl group having 1 to 10 carbon atoms, and the asterisk represents
a binding site to L.
[0027] In the formula (S-7), R
12 is preferably a hydrogen atom, X
1 is preferably a hydrogen atom or a halogen atom, X
2 is preferably a halogen atom independently of X
1, and X
3 is preferably a hydrogen atom. In addition, in a case where S is a group represented
by the formula (S-7), L is preferably a group represented by *-(CH
2)
n- wherein * is a binding site to the formula (S-7), and n is an integer of 1 to 5
and preferably 2 or 3.
[0028] In addition, another example which can be adopted as a substrate S includes a group
represented by the following formula (S-8).
wherein X
4 is a halogen atom or a methyl group, R
13 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the asterisk
represents a binding site to L.
[0029] In the formula (S-8), X
4 is preferably a halogen atom and R
13 is preferably a methyl group. In addition, in a case where S is a group represented
by the formula (S-7), L is preferably a group presented by *-(CH
2)
n- wherein * is a binding site to the formula (S-7), and n is an integer of 1 to 5
and preferably n is 3.
[0030] Examples of the radioactive labeled compound of the general formula (1) obtained
from the labeling precursor compound of the present invention include various compounds
which are used as a radiopharmaceutical, preferably a diagnostic drug by a positron
emission tomography (PET) method. For example, in a case where the formula (S-3) is
adopted as the substrate S, an amyloid affinity compound disclosed in
WO 2007/135890 A may be mentioned. In addition, in a case where the formula (S-4) is adopted as the
substrate S, a compound for imaging myocardial perfusion (for example, Flurpiridaz
and the like) disclosed in
WO 2005/079391 A may be mentioned by way of example. In addition, in a case where the formula (S-5)
is adopted as the substrate S, a compound for imaging amyloid, such as Florbetapir
and Florbetaben may be mentioned by way of example. In addition, in a case where the
formula (S-6) is adopted as the substrate S, a compound for imaging a tumor, such
as O-(2-fluoroethyl)-L-tyrosine (FET) may be mentioned by way of example. In addition,
in a case where the formula (S-7) is adopted as the substrate S, a compound for image
diagnosis of adrenal gland disease disclosed in
WO 2015/199205 A may be mentioned by way of example. In addition, in a case where the formula (S-7)
is adopted as the substrate S, a compound for mapping a monoamine reuptake site (for
example, FP-CIT) disclosed in
WO 99/01184 A may be mentioned by way of example.
[0031] The radioactive fluorine-labeling precursor compound of the present invention can
be produced by, for example, acting a sulfonyl fluoride corresponding to a leaving
group and diazabicycloundecene (DBU) on a compound (OH form) in which a hydroxyl group
is bonded to a site where radioactive fluorine is to be introduced, as shown in SCHEME
1 below. Note that, in SCHEME 1 below, S, L, R
1 to R
3, and p are the same as those mentioned above concerning the general formula (2),
and X is a halogen atom.
2. Production method of radioactive fluorine-labeled compound using radioactive fluorine-labeling
precursor compound
[0032] According to the present invention, a radioactive fluorine-labeled compound represented
by the general formula (1) can be produced by a step of allowing a radioactive fluorine-labeling
precursor compound represented by the general formula (2) to react with [
18F]fluoride ion (radioactive fluorine labeling reaction step) .
[0033] The radioactive fluorine labeling reaction is preferably performed in the presence
of a base in an inert solvent. Specifically, the compound represented by the general
formula (1) can be obtained by performing the reaction in an appropriate solvent such
as an aprotic solvent, e.g., acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide
at a temperature of 20 to 120°C using a [
18F]fluoride ion aqueous solution produced from [
18O]water by cyclotron as the [
18F]fluoride ion and using a base exemplified by tetrabutylammonium or potassium carbonate/Kryptofix
222. The radioactive fluorine labeling reaction can be performed with a synthesis
apparatus equipped with a reaction vessel and a shield. In addition, the synthesis
apparatus may be an automatic synthesis apparatus in which all steps are automated.
[0034] In the above reaction step, by-products such as an unreacted precursor compound (that
is, a compound represented by the general formula (2)) and an OH form represented
by the following general formula (3) coexist with the target compound represented
by the general formula (1).
wherein S and L are the same as in the general formula (1).
[0035] The purification of the target compound represented by the general formula (1) can
be performed in accordance with a solid phase extraction method using a reverse-phase
cartridge column. Specifically, the unreacted precursor compound (that is, the compound
represented by the general formula (2)) is usually higher in lipophilicity, in other
words, higher in hydrophobicity than the target compound represented by the general
formula (1). Accordingly, a method utilizing such a difference in hydrophobicity may
be used, which may be exemplified by a method in which a reaction mixture obtained
in the radioactive fluorine labeling reaction step is added to a reverse-phase cartridge
column filled with octadecyl silica gel or the like, [
18F]fluoride ion is separated, and then an appropriate elution solvent is allowed to
pass through the above column, such that the compound of the general formula (1) which
is the object compound can be eluted to be separated and collected. Examples of the
elution solvent include water-soluble solvents such as acetonitrile, ethanol, t-butanol
and methanol, or a mixed liquid of these with water. The compound of the general formula
(1) which is the collected target compound can be subjected to deprotection and the
like, if necessary, to be an object compound.
Examples
[0036] Hereinafter, the present invention is described more specifically by way of examples;
however, the present invention is not limited only to the following examples.
[0037] It is to be noted that in the following examples, the names of individual compounds
used in experiments are defined as shown in Table 1.
[0038] In the examples, the molecular structure of the individual compounds was identified
based on nuclear magnetic resonance (NMR) spectra. AVANCE III HD (manufactured by
BRUKER Japan K.K.) was used as an NMR apparatus and deuterated chloroform was used
as a solvent.
1H-NMR was measured at a resonance frequency of 500 MHz.
13C-NMR was measured at a resonance frequency of 125 MHz. All chemical shifts are given
in terms of ppm on a delta scale (δ). Fine splittings of signals were indicated using
abbreviations (s: singlet, d: doublet, t: triplet, dd: double doublet, dt: double
triplet, dq: double quartet, m: multiplet, and br: broad).
[0039] Hereinafter, the term "room temperature" in the examples means 25°C.
[0040] In a synthesis example of each compound, each step in the compound synthesis was
repeated plural times if necessary to secure an amount required for use as an intermediate
or the like in other syntheses.
Example 1: Synthesis of precursor compound 1
[0041] According to the following scheme, 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-(dibutylcarbamoyl)benzenesulfonate
(precursor compound 1) was synthesized.
Step 1: Synthesis of 4-(dibutylcarbamoyl)benzenesulfonic acid fluoride
[0042] Dibutylamine (280 µL, 1.60 mmol) was dissolved in dichloromethane (12 mL), triethylamine
(0.25 mL, 1.8 mmol) was added to the resulting solution, the solution was cooled to
0°C, and then 4-fluorosulfonyl benzoic acid chloride (233 mg, 1.05 mmol) was added
to the cooled solution and the solution was stirred at 0°C for 5 hours. After completion
of the reaction, the reaction solution was added to 1 mol/L hydrochloric acid and
extraction with ethyl acetate was performed two times. The combined ethyl acetate
layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a
saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated
under reduced pressure, and then the obtained crude product was purified by silica
gel column chromatography (eluent: hexane/ethyl acetate = 3 : 1) to obtain 4-(dibutylcarbamoyl)benzenesulfonic
acid fluoride (191 mg, 0.61 mmol).
1H-NMR: δ 8.06(d,2H,J=8.5Hz), 7.59(d,2H,J=8.0Hz), 3.51(t,2H,J=7.5Hz), 3.13(t,2H,J=7.5Hz),
1.69-1.63(m,2H), 1.58(m,2H), 1.52-1.46(m,2H), 1.43-1.38(m,2H), 1.19-1.11(m,2H), 0.99(t,3H,J=7.5Hz),
0.81(t,3H,J=7.5Hz)
Step 2: Synthesis of 2-([1,1'-biphenyl]-4-ylmethoxy)ethanol
[0043] Potassium t-butoxide (444 mg, 4.4 mmol) was dissolved in ethylene glycol (4.4 mL,
78.9 mmol), a solution obtained by dissolving 4-(bromomethyl)-1,1'-biphenyl (1.8 g,
4.386 mmol) in tetrahydrofuran (20 mL) was added to the resulting solution, and the
solution was stirred at 65°C for 6.5 hours. Potassium t-butoxide (101 mg, 1.1 mmol)
was added and stirred at 65°C for 1.5 hours. After completion of the reaction, the
reaction solution was added to 0.1 mol/L hydrochloric acid and extraction with ethyl
acetate was performed two times. The combined ethyl acetate layer was washed with
water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure,
and then the obtained crude product was purified by silica gel column chromatography
(eluent: hexane/ethyl acetate = 3 : 1) to obtain 2-([1,1'-biphenyl]-4-ylmethoxy)ethanol
(967 mg, 4.24 mmol).
1H-NMR: δ 7.60-7.58(m, 4H), 7.46-7.41(m, 4H), 7.37-7.34(m, 1H), 4.61(s, 2H), 3.79(dd,
2H, J=6.0,4.0Hz), 3.64(dd,2H,J=6.0,4.0Hz)
Step 3: Synthesis of precursor compound 1
[0044] 2-([1,1'-biphenyl]-4-ylmethoxy)ethanol (52 mg, 0.22 mmol) was dissolved in acetonitrile
(2.0 mL), the solution was cooled to 0°C, and then diazabicycloundecene (79 µL, 0.50
mmol) and 4-(dibutylcarbamoyl)benzenesulfonic acid fluoride (88 mg, 0.26 mmol) were
added to the cooled solution and the solution was stirred at room temperature for
1 hour. After completion of the reaction, water was added to the reaction solution
and extraction with ethyl acetate was performed two times. The combined ethyl acetate
layer was washed with water and a saturated saline solution, dried with anhydrous
magnesium sulfate, and concentrated under reduced pressure, and then the obtained
crude product was purified by silica gel column chromatography (eluent: hexane/ethyl
acetate = 75/25) to obtain the precursor compound 1 (70 mg, 0.14 mmol).
1H-NMR: δ 7.95(d,2H,J=8.5Hz), 7.60-7.56(m,4H), 7.49(d,2H,J=8.5Hz), 7.46-7.43(m,2H),
7.37-7.35(m,3H), 4.54(s,2H), 4.25(t,2H,J=4.5Hz), 3.70(t,2H,J=4.5Hz), 3.49(t,2H,J=7.5Hz),
3.11(t,2H,J=7.5Hz), 1.68-1.60(m,2H), 1.49-1.36(m,4H), 1.18-1.08(m,2H) 0.98(t,3H,J=7.3Hz),
0.78(t, 3H, J=7.3Hz)
Example 2: Synthesis of precursor compound 2
[0045] According to the following scheme, 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-(dihexylcarbamoyl)benzenesulfonate
(precursor compound 2) was synthesized.
Step 1: Synthesis of 4-(dihexylcarbamoyl)benzenesulfonic acid fluoride
[0046] Dihexylamine (176 µL, 0.75 mol) was dissolved in dichloromethane (12 mL), triethylamine
(0.13 mL, 1.25 mmol) was added to the resulting solution, the solution was cooled
to 0°C, and then 4-fluorosulfonyl benzoic acid chloride (151 mg, 0.68 mmol) was added
to the cooled solution and the solution was stirred at 0°C for 3 hours. After completion
of the reaction, the reaction solution was added to 1 mol/L hydrochloric acid and
extraction with ethyl acetate was performed two times. The combined ethyl acetate
layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a
saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated
under reduced pressure, and then the obtained crude product was purified by silica
gel column chromatography (eluent: hexane/ethyl acetate = 3 : 1) to obtain 4-(dihexylcarbamoyl)benzenesulfonic
acid fluoride (181 mg, 0.49 mmol).
δ 8.06(d,2H,J=8.5Hz), 7.59(d,2H,J=8.0Hz), 3.49(t,2H,J=7.5Hz), 3.12(t,2H,J=7.5Hz),
1.70-1.64(m,2H), 1.52-1.48(m,2H), 1.40-1.32(m,6H) 1.25-1.18(m,2H), 1.18-1.08(m,4H),
0.93-0.90(m,3H), 0.84(t,3H,J=7.3z)
Step 2: Synthesis of precursor compound 2
[0047] 2-([1,1'-biphenyl]-4-ylmethoxy)ethanol (50 mg, 0.22 mmol) was dissolved in acetonitrile
(2.0 mL), the solution was cooled to 0°C, and then diazabicycloundecene (79 µL, 0.50
mmol) and 4-(dibutylcarbamoyl)benzenesulfonic acid fluoride (85 mg, 0.22 mmol) were
added to the cooled solution and the solution was stirred at room temperature for
1 hour. After completion of the reaction, water was added to the reaction solution
and extraction with ethyl acetate was performed two times. The combined ethyl acetate
layer was washed with water and a saturated saline solution, dried with anhydrous
magnesium sulfate, and concentrated under reduced pressure, and then the obtained
crude product was purified by silica gel column chromatography (eluent: hexane/ethyl
acetate = 3 : 1) to obtain the precursor compound 2 (83 mg, 0.14 mmol).
1H-NMR: δ 7.96(d,2H,J=8.5Hz), 7.60-7.57(m,4H), 7.48(d,2H,J=8.5Hz), 7.46-7.42(m,2H),
7.37-7.33(m,3H), 4.54(s,2H), 4.25(t,2H,J=4.8Hz), 3.70(t,2H,J=4.8Hz), 3.47(t,2H,J=7.8Hz),
3.10(t,2H,J=7.5Hz), 1.68-1.60(m,2H), 1.49-1.30(m,6H), 1.25-1.17(m,2H), 1.17-1.08(m,4H)
0.93-0.90(m,3H), 0.83(t,3H,J=7.3z)
Example 3: Synthesis of precursor compound 3
[0048] According to the following scheme, 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-(didodecylcarbamoyl)benzenesulfonate
(precursor compound 3) was synthesized.
Step 1: Synthesis of 4-(didodecylcarbamoyl)benzenesulfonic acid fluoride
[0049] Didodecylamine (500 mg, 2.70 mmol) was dissolved in dichloromethane (23 mL), triethylamine
(0.63 mL, 4.50 mmol) was added to the resulting solution, the solution was cooled
to 0°C, and then 4-fluorosulfonyl benzoic acid chloride (500 mg, 2.25 mmol) was added
to the cooled solution and the solution was stirred at room temperature for 18 hours.
After completion of the reaction, 1 mol/L hydrochloric acid was added to the reaction
solution and extraction with ethyl acetate was performed three times. The combined
ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate
solution and a saturated saline solution, dried with anhydrous sodium sulfate, and
concentrated under reduced pressure, and then the obtained crude product was purified
by silica gel column chromatography (eluent: toluene/ethyl acetate = 40 : 1) to obtain
4-(didodecylcarbamoyl)benzenesulfonic acid fluoride (627 mg, 1.16 mmol).
1H-NMR: δ 8.05(d,2H,J=8.3Hz), 7.59(d,2H,J=8.3Hz), 3.49(t,2H,J=7.6Hz), 3.11(t,2H,J=7.4Hz),
1.65(br,2H), 1.49(br, 2H), 1.35-1.09(m,36H), 0.88(t,6H,J=6.7Hz)
Step 2: Synthesis of 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-(didodecylcarbamoyl)benzenesulfonate
(precursor compound 3)
[0050] 2-([1,1'-biphenyl]-4-ylmethoxy)ethanol (32 mg, 0.14 mmol) was dissolved in dichloromethane
(1.4 mL), the solution was cooled at 0°C, and then diazabicycloundecene (50 µL, 0.33
mmol) and 4-(didodecylcarbamoyl)benzenesulfonic acid fluoride (90 mg, 0.17 mmol) were
added to the cooled solution and the solution was stirred at room temperature for
18 hours. After completion of the reaction, water was added to the reaction solution
and extraction with chloroform was performed three times. The combined ethyl acetate
layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure,
and then the obtained crude product was purified by silica gel column chromatography
(eluent: chloroform) to obtain 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-(didodecylcarbamoyl)benzenesulfonate
(54 mg, 0.07 mmol).
1H-NMR:δ 7.96-7.94(m,2H), 7.60-7.57(m,4H), 7.49-7.42(m,4H), 7.37-7.35(m,3H), 4.54(s,2H),
4.25(t,2H,J=4.6Hz), 3.70(t,2H,J=4.6Hz), 3.47(t,2H,J=7.6Hz), 3.09(t,2H,J=7.2Hz), 1.63(br,2H),1.46(br,2H),
1.35-1.07(m,36H), 0.88-0.87(m, 6H)
Example 4: Synthesis of precursor compound 4
[0051] According to the following scheme, 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-(dioctadecylcarbamoyl)benzenesulfonate
(precursor compound 4) was synthesized.
Step 1: Synthesis of 4-(dioctadecylcarbamoyl)benzenesulfonic acid fluoride
[0052] Dioctadecylamine (282 mg, 0.54 mmol) was dissolved in dichloromethane (1 mL), triethylamine
(0.13 mL, 0.90 mmol) was added to the resulting solution, the solution was cooled
to 0°C, and then 4-fluorosulfonyl benzoic acid chloride (100 mg, 0.45 mmol) was added
to the cooled solution and the solution was stirred at room temperature for 18 hours.
After completion of the reaction, water was added to the reaction solution and extraction
with chloroform was performed three times. The combined chloroform layer was dried
with anhydrous sodium sulfate, and concentrated under reduced pressure, and then the
obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl
acetate = 5/1) to obtain 4-(dioctadecylcarbamoyl)benzenesulfonic acid fluoride (208
mg, 0.29 mmol).
1H-NMR:δ 8.05(d,2H,J=8.4Hz), 7.60(d,2H,J=8.4Hz), 3.49(t,2H,J=7.6Hz), 3.11(t,2H,J=7.6Hz),
1.66(br,2H), 1.49(br,2H), 1.36-1.10(m, 60H), 0.88(t, 6H, J=7.0)
Step 2: Synthesis of 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-(dioctadecylcarbamoyl)benzenesulfonate
(precursor compound 4)
[0053] 2-([1,1'-biphenyl]-4-ylmethoxy)ethan-1-ol (30 mg, 0.13 mmol) was dissolved in dichloromethane
(1.3 mL), the solution was cooled to 0°C, and then diazabicycloundecene (47 µL, 0.32
mmol) and 4-(dioctadecylcarbamoyl)benzenesulfonic acid fluoride (112 mg, 0.16 mmol)
were added to the cooled solution and the solution was stirred at room temperature
for 18 hours. After completion of the reaction, water was added to the reaction solution
and extraction with chloroform was performed three times. The combined chloroform
layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure,
and then the obtained crude product was purified by silica gel column chromatography
(eluent: chloroform) to obtain 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-(dioctadecylcarbamoyl)benzenesulfonate
(63 mg, 0.07 mmol).
1H-NMR:δ 7.96-7.94(m,2H), 7.60-7.57(m,4H), 7.49-7.42(m,4H), 7.37-7.35(m,3H), 4.54(s,2H),
4.25(t,2H,J=4.7Hz), 3.70(t,2H,J=4.7Hz), 3.50-3.45(m,2H), 3.10-3.08(m,2H), 1.64-1.62(m,2H),
1.47-1.46(m,2H), 1.34-1.04(m,60H), 0.88(t,6H,J=6.75Hz)
Comparative Example 1: Synthesis of 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-methylbenzenesulfonate
(precursor compound 5)
[0054] According to the following scheme, the precursor compound 5 was synthesized.
Step 1: Synthesis of 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl-4-methylbenzenesulfonate
[0055] 2-([1,1'-biphenyl]-4-ylmethoxy)ethanol (55 mg, 0.24 mmol) was dissolved in dichloromethane
(2 mL), and 1,4-diazabicyclo[2,2,2]octane (86 mg, 0.77 mmol) and p-toluenesulfonyl
chloride (69 mg, 0.36 mmol) were added to the resulting solution and the solution
was stirred at room temperature for 4.5 hours. After completion of the reaction, water
was added to the reaction solution and extraction with ethyl acetate was performed
two times. The combined ethyl acetate layer was dried with anhydrous magnesium sulfate,
and concentrated under reduced pressure, and then the obtained crude product was purified
by silica gel column chromatography (eluent: hexane/ethyl acetate = 3 : 1) to obtain
4-methylbenzenesulfonic acid 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl (64 mg, 0.17 mmol).
1H-NMR:δ 7.81(d, 2H, J=8.0Hz), 7.60-7.54(m,4H), 7.47-7.43(m,2H), 7.37-7.30(m,5H), 4.53(s,2H),
4.22(t,2H,J=4.8Hz), 3.70(t,2H,J=4.8Hz), 2.43(s,3H)
Comparative Example 2: Synthesis of precursor compound 6
[0056] According to the following scheme, 4-(2-cyclohexylethyl)benzenesulfonic acid 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl
(precursor compound 6) was synthesized.
Step 4: Synthesis of precursor compound 6
[0057] 2-([1,1'-diphenyl]-4-ylmethoxy)-ethanol (50.6 mg, 0.222 mmol) was dissolved in dichloromethane
(2.0 mL) and cooled to 0°C, and then the resultant solution was supplemented with
a solution in which 1,4-diazabicyclo[2.2.2]octane (37.4 mg, 0.333 mmol) was dissolved
in dichloromethane (2.0 mL) together with 4-(2-cyclohexyl-ethyl)-benzenesulfonyl chloride
(76.4 mg, 0.266 mmol) obtained by performing the Steps 1 to 3 in accordance with the
method described in Example 1 of
WO 2011/006610 A. After stirring for 30 minutes, the reaction was stopped by addition of a saturated
aqueous sodium hydrogen carbonate solution and extraction with dichloromethane was
performed three times. The combined dichloromethane layer was washed with water and
a saturated saline solution, dried over sodium sulfate, and concentrated under reduced
pressure. The obtained crude product was purified by silica gel column chromatography
(eluent: hexane/ethyl acetate = 4 : 1) to obtain 4-(2-cyclohexylethyl)benzenesulfonic
acid 2-([1,1'-biphenyl]-4-ylmethoxy)ethyl (75.6 mg, 0.158 mmol).
1H-NMR:δ 7.81(d,2H,J=8.4Hz), 7.59-7.55(m,4H), 7.44(t,2H,J=7.6Hz), 7.37-7.30(m,5H),
4.53(s,2H), 4.23(t,2H,J=4.8Hz), 3.70(t,2H,J=4.8Hz), 2.67(t,2H,J=8.2Hz), 1.74-1.64(m,5H),
1.51-1.47(m,2H), 1.25-1.13(m,4H), 0.96-0.88(m,2H)
Reference Example 1: Synthesis of unlabeled compound 1
[0058] According to the following scheme, 4-([2-fluoroethoxy]methyl)-1,1'-biphenyl (unlabeled
compound 1) was synthesized.
Step 1: Synthesis of 4-([2-fluoroethoxy]methyl)-1,1'-biphenyl
[0059] 2-Fluoroethanol (86 mg, 0.77 mmol) was dissolved in tetrahydrofuran (1.4 mL) and
cooled to 0°C, and sodium hydride (3.2 mg, 0.14 mmoL) was added to the cooled solution
and the solution was stirred for 10 minutes. Subsequently, 4-(bromomethyl)-1,1'-biphenyl
(50 mg, 0.20 mmol) was added and stirred at room temperature for 18 hours. After completion
of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction
solution and extraction with chloroform was performed three times. The combined chloroform
layer was washed with water, dried with anhydrous sodium sulfate, concentrated under
reduced pressure, and then the obtained crude product was purified by silica gel column
chromatography (eluent: hexane/ethyl acetate = 10/1) to obtain 4-([2-fluoroethoxy]methyl)-1,1'-biphenyl
(5.8 mg, 0.03 mmol).
1H-NMR:δ 7.60-7.58(m,4H), 7.45-7.42(m,4H), 7.36-7.33(m, 1H), 4.65(s, 2H), 4.61(dt,2H,J=47.7Hz,4.2Hz),
3.76(dt,2H,J=29.4Hz,4.2Hz)
Example 5: Preparation of radioactive fluorinated 4-[(2-[18F]fluoroethoxy)methyl]-1,1'-biphenyl using precursor compounds 1 to 4
[0060] An aqueous potassium carbonate solution (50 µmol/L, 0.2 mL) and a solution of Kryptofix
222 (trade name, manufactured by Merck KGaA) (12 mg, 37.2 µmol) dissolved in acetonitrile
(0.6 mL) were added to [
18F]fluoride ion-containing [
18O]water. The resulting solution was heated at 110°C in a flow of argon gas to evaporate
water, and then supplemented with acetonitrile (0.5 mL x 3) and azeotropically evaporated
to dryness. A solution of each of the precursor compounds 1 to 6 (8 µmol) synthesized
in accordance with the methods shown in Examples 1 to 6 dissolved in acetonitrile
(0.5 mL) was added to the dried residue, and the mixture was heated at 90°C for 5
minutes. After completion of the reaction, the mixture was analyzed by a thin layer
chromatography (TLC) under the following conditions, and then water for injection
(10 mL) was added to the mixture. Then, the mixture was allowed to pass through Sep-Pak
(registered trademark) C18 Plas (trade name, manufactured by Nippon Waters K.K.),
such that 4-[(2-[
18F]fluoroethoxy)methyl]-1,1'-biphenyl was absorbed and collected onto the corresponding
column. After the column was washed with water (10 mL), a mixed liquid (4 mL) of water/acetonitrile
= 1:3 was allowed to pass through the column to elute 4-[(2-[
18F]fluoroethoxy)methyl]-1,1'-biphenyl.
[0061] The 4-[(2-[
18F]fluoroethoxy)methyl]-1,1'-biphenyl obtained by the operation described above was
subjected to an HPLC analysis under the following conditions. Note that the identification
was performed by confirming whether or not its Rf value on the TLC plate is the same
as that of the unlabeled compound of 4-[(2-fluoroethoxy)methyl]-1,1'-biphenyl synthesized
with Reference Example 1.
TLC condition
[0062]
Plate: TLC glass plate Silica gel 60F254
Developing solvent: hexane/ethyl acetate = 3 : 1
HPLC condition
[0063]
Column: CAPCELLPAKC18MGII (trade name, manufactured by Shiseido Company, Limited,
particle size: 5 µm, size: 4.6 mmϕ x 150 mm)
Mobile phase: 20 mmol/L ammonium acetate buffer solution (pH = 6.0)/acetonitrile =
70/30 → 30/70 (0 → 30 minutes), 30/70 (30 → 45 minutes), 30/70 → 1/99 (45 → 46 minutes),
1/99 (46 → 100 minutes)
Flow rate: 1.0 mL/min
Detector: ultraviolet-visible absorption photometer (detection wavelength: 254 nm)
Comparative Example 3: Preparation of radioactive fluorinated 4-[(2-[18F]fluoroethoxy)methyl]-1,1'-biphenyl using conventional precursor compound
[0064] The preparation was performed in the same manner as in Example 5 except that, as
a precursor compound, the precursor compound 5 or 6 synthesized in accordance with
the method shown in Comparative Example 1 or 2 was used.
Evaluation 1: Evaluation of labeling reaction for fluorine-labeled compound
[0065] Table 2 shows the amounts of radioactivity used in Example 5 and Comparative Example
3, and the amount of radioactivity and [
18F] fluorination rate of the obtained product (4-[(2-[
18F]fluoroethoxy)methyl]-1,1'-biphenyl). A peak area ratio of 4-[(2-[
18F]fluoroethoxy)methyl]-1,1'-biphenyl subjected to the TLC analysis after completion
of the reaction was taken as a [
18F] fluorination rate.
[0066] As shown in Table 2, by using the precursor compounds 1 to 4 of the Examples, the
approximately same [
18F] fluorination rate as those of the conventional precursor compounds 5 and 6 was
obtained.
Table 2
|
Radioactivity of [18F] F- water used (Value corrected at start of synthesis) |
Amount of radioactivity of product (Measurement time) |
[18F] fluorination rate at the time of completing reaction |
Precursor Compound 1 |
443 MBq |
241 MBq (44 minutes after start of synthesis) |
75% |
Precursor Compound 2 |
234 MBq |
177 MBq (44 minutes after start of synthesis) |
82% |
Precursor Compound 3 |
488 MBq |
250 MBq (35 minutes after start of synthesis) |
67% |
Precursor Compound 4 |
676 MBq |
276 MBq (41 minutes after start of synthesis) |
65% |
Precursor Compound 5 |
158 MBq |
78.4 MBq (65 minutes after start of synthesis) |
78% |
Precursor Compound 6 |
507 MBq |
256 MBq (60 minutes after start of synthesis) |
66% |
Evaluation 2: Evaluation of impurities
[0067] Table 3 shows the evaluation results obtained by an HPLC analysis of the amount of
nonradioactive impurities in the 4-[(2-[
18F]fluoroethoxy)methyl]-1,1'-biphenyl obtained in Example 5 and Comparative Example
3. A mixed amount of the precursor compound was quantitatively determined with a calibration
curve prepared using a standard sample. In addition, a collection rate was shown as
a collection rate with respect to the amount of precursor compound used in the radioactive
fluorination reaction. The amount of impurities having unknown structures was converted
to the amount of OH form (2-([1,1'-biphenyl]-4-ylmethoxy)ethan-1-ol) for evaluation.
[0068] As a result, as shown in Table 3, all of the precursor compounds 1 to 4 of the Examples
showed smaller amounts of precursor contamination than the conventional precursor
compounds 5 and 6. In addition, the precursor compounds 1, 3, and 4 were also smaller
in amounts of nonradioactive impurities having unknown structures than the conventional
compound.
Table 3
|
Mixed amount of precursor compound (Collection rate) |
Mixed amount of nonradioactive impurities* having unknown structures (Collection rate) |
Precursor Compound 1 |
11 µg/mL (1%) |
335 µg/mL (32%) |
Precursor Compound 2 |
12 µg/mL (1%) |
401 µg/mL (34%) |
Precursor Compound 3 |
Lower than detection limit * (0%) |
310 µg/mL (21%) |
Precursor Compound 4 |
Lower than detection limit * (0 %) |
290 µg/mL (26%) |
Precursor Compound 5 |
303µg/mL (40%) |
354 µg/mL (46%) |
Precursor Compound 6 |
60µg/mL (6%) |
191 µg/mL (20%) |
*Detection limit: 1 µg/mL |
Example 6: Synthesis of precursor compound 7
[0069] According to the following scheme, 2-(4-(6-imidazo[1,2-a]pyridine-2-yl)phenoxy)ethyl-4-(didodecylcarbamoyl)benzenesulfonate
(precursor compound 7) was synthesized.
Step 6: Synthesis of precursor compound 7
[0070] 2-[4'-(2-hydroxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (100 mg, 0.263 mmol)
obtained by performing the Steps 1 to 5 in accordance with the method described in
Example 11-14 of
WO 2007/135890 A was dissolved in acetonitrile (10.0 mL) and cooled to 0°C, and then the resultant
solution was supplemented with a solution in which 1,8-diazabicyclo[5.4.0]undecene
(78.6 µL, 0.526 mmol) was dissolved in acetonitrile (2.0 mL) together with 4-didodecylcarbamoyl
benzene sulfonic acid fluoride (185 mg, 0.342 mmol) obtained by performing the Step
1 in accordance with the method described in Example 3. After warming to room temperature
and stirring for 3 hours, the reaction was stopped by addition of water and extraction
with ethyl acetate was performed three times. The combined ethyl acetate layer was
washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated
saline solution, dried over sodium sulfate, and concentrated under reduced pressure.
The obtained crude product was purified by silica gel column chromatography (eluent:
chloroform) to obtain 2-(4-(6-imidazo[1,2-a]pyridine-2-yl)phenoxy)ethyl-4-(didodecylcarbamoyl)benzenesulfonate
(198 mg, 0.220 mmol) (precursor compound 7).
1H-NMR:δ 8.37(s, 1H), 7.98(d,2H,J=8.4Hz), 7.84(d,2H,J=8.8Hz), 7.7(s, 1H), 7.52(d,2H,J=8.4Hz),
7.40(d, 1H, J=9.4Hz), 7.32(d, 1H, J=9.4Hz), 6.88(d,2H,J=8.8Hz), 4.42(t,2H,J=4.6Hz),
3.48(t,2H,J=4.6Hz), 3.48(t,2H,J=7.6Hz), 3.11(t,2H,J=7.6Hz), 1.65-1.45(m,12H), 1.36-1.08(m,29H),
0.89-0.86(m, 5H)
Example 7: Synthesis of amyloid beta imaging agent
[0071] An amyloid beta imaging agent, 2-[4'-(2"-[
18F]fluoroethoxy)phenyl]-6-iodoimidazo[1, 2-a]pyridine (
18F labeled compound 1-9 in
WO 2007/135890 A) was produced by using the precursor compound 7 synthesized in accordance with the
method shown in Example 6.
[0072] An aqueous potassium carbonate solution (66 µmol/L, 0.3 mL) and a solution of Kryptofix
222 (trade name, manufactured by Merck KGaA) (15 mg, 39.9 µmol) dissolved in acetonitrile
(1.5 mL) were added to [
18F]fluoride ion-containing [
18O]water (the amount of radioactivity: 533 MBq, the value corrected at the start of
synthesis). The resulting solution was heated at 110°C in a flow of argon gas to evaporate
water, and then supplemented with acetonitrile (0.5 mL x 3) and azeotropically evaporated
to dryness. A solution of the precursor compound 7 (30 mg, 33 µmol) synthesized with
the example described above dissolved in dimethyl sulfoxide (0.5 mL) was added to
the mixture and heated at 110°C for 10 minutes. After completion of the reaction,
water for injection (10 mL) was added to the mixture, and the mixture was allowed
to pass through Sep-Pak (registered trademark) C18 Plas (trade name, manufactured
by Nippon Waters K.K.). Then, the column was washed with water (10 mL) and a mixed
liquid (2 mL) of water/acetonitrile = 1:1, and then 2-[4'-(2"-[
18F]fluoroethoxy)phenyl]-6-iodoimidazo[1, 2-a]pyridine was eluted with a mixed liquid
(3 mL) of water/acetonitrile = 1 : 3. The obtained amount of radioactivity was 186
MBq (58 minutes after the start of synthesis). In addition, as a result of the HPLC
analysis under the following conditions, it was confirmed that 4 µg/mL of the unreacted
precursor compound 7 was mixed. In case where a toluene sulfonic acid ester group
is used as a leaving group, instead of the sulfonic acid ester group having an alkyl
amide tag introduced according to the present invention, a mixed amount of the unreacted
precursor compound was 650 µg/mL. Thus, it was confirmed that an amyloid beta imaging
agent low in contamination of the unreacted precursor compound was able to be synthesized
by the present invention even without the HPLC purification.
HPLC condition
[0073]
Column: YMC-Pack Pro C8 (trade name, manufactured by YMC CO., LTD., particle size:
5 µm, size: 4.6 mmϕ × 150 mm)
Mobile phase: 10 mmol/L ammonium formate buffer solution (pH3)/acetonitrile = 100/0
→ 70/30 (0 → 20 minutes), 70/3 → 10/90 (20 → 30 minutes), 10/90 (30 → 70 minutes)
Flow rate: 1.0 mL/min
Detector: ultraviolet-visible absorption photometer (detection wavelength: 260 nm)
Example 8: Synthesis of precursor compound 8
[0074] According to the following scheme, 2-(2-{5-[(1H-imidazole-1-yl)methyl]pyridine-3-yl}-6-chloro-5-fluoro-1H-benzimidazole-1-yl)ethyl-4-(didodecylcarbamoyl)benzenesulfonate
(precursor compound 8) was synthesized.
Step 1: Synthesis of precursor compound 8
[0075] 2-{6-chloro-5-fluoro-2-[5-(imidazole-1-ylmethyl)pyridine-3-yl]benzimidazole-1-yl}ethanol
(57.3 mg, 0.154 mmol) obtained by performing the Steps 1 to 10 in accordance with
the method described in Example 2 of
WO 2015/199205 A was dissolved in dichloromethane (0.54 mL) and cooled to 0°C, and then the resultant
solution was supplemented with a solution in which 1,8-diazabicyclo[5.4.0]undecene
(55.3 µL, 0.370 mmol) was dissolved in dichloromethane (1.0 mL) together with 4-didodecylcarbamoyl
benzene sulfonic acid fluoride (100 mg, 0.185 mmol) obtained by performing the Step
1 in accordance with the method described in Example 3. After warming to room temperature
and stirring for 1 hour, the reaction was stopped by addition of water and extraction
with dichloromethane was performed three times. The combined dichloromethane layer
was washed with water and a saturated saline solution, dried over sodium sulfate,
and concentrated under reduced pressure. The obtained crude product was purified by
silica gel column chromatography (eluent: dichloromethane) to obtain 2-(2-{5-[(1H-imidazole-1-yl)methyl]pyridine-3-yl}-6-chloro-5-fluoro-1H-benzimidazole-1-yl)ethyl-4-(didodecylcarbamoyl)benzenesulfonate
(precursor compound 8) (94 mg, 0.105 mmol).
1H-NMR:δ 8.85(d, 1H, J=2.1Hz), 8.63(d, 1H, J=2.1Hz), 7.84(dd, 1H, J=2.1, 2.1Hz), 7.66(d,2H,J=8.4Hz),
7.66(s, 1H), 7.59(d, 1H, J=9.0Hz), 7.43(d,2H,J=8.4Hz), 7.40(d, 1H, J=6.1Hz), 7.14(t,
1H, J=1.2Hz), 7.00(t, 1H, J=1.2Hz), 5.29(s, 2H), 4.47(t, 2H, 5.2Hz) 4.25(t,2H,J=5.2Hz),
3.47(t,2H,J=7.5Hz), 3.07(t,2H,J=7.5Hz), 1.65(br,2H), 1.47-1.43(m,2H), 1.36-1.06(m,36H),
0.88-0.86(m,6H)
Example 9: Synthesis of aldosterone synthase imaging agent
[0076] An aldosterone synthase imaging agent, 6-chloro-5-fluoro-1-(2-[
18F]fluoroethyl)-2-[5-(imidazole-1-ylmethyl)pyridine-3-yl]benzimidazole (
18F labeled compound 100 in
WO 2015/199205 A) was produced by using the precursor compound 8 synthesized with the method shown
in Example 8.
[0077] An aqueous potassium carbonate solution (50 µmol/L, 0.25 mL) and a solution of Kryptofix
222 (trade name, manufactured by Merck KGaA) (14 mg, 37.2 µmol) dissolved in acetonitrile
(0.7 mL) were added to [
18F]fluoride ion-containing [
18O]water (the amount of radioactivity: 533 MBq, the value corrected at the start of
synthesis). The resulting solution was heated at 110°C in a flow of argon gas to evaporate
water, and then supplemented with acetonitrile (0.5 mL x 3) and azeotropically evaporated
to dryness. A solution of the precursor compound 7 (8.5 mg, 9.5 µmol) synthesized
with the example described above dissolved in dimethyl sulfoxide (0.5 mL) was added
to the mixture and heated at 110°C for 10 minutes. After completion of the reaction,
water for injection (10 mL) was added to the mixture, and the mixture was allowed
to pass through Sep-Pak (registered trademark) C18 Plas (trade name, manufactured
by Nippon Waters K.K.). Then, the column was washed with water (10 mL), and then 6-chloro-5-fluoro-1-(2-[
18F]fluoroethyl)-2-[5-(imidazole-1-ylmethyl)pyridine-3-yl]benzimidazole was eluted with
a mixed liquid (5 mL) of water/acetonitrile = 1:1. The obtained amount of radioactivity
was 141 MBq (44 minutes after the start of synthesis). In addition, as a result of
the HPLC analysis under the following conditions, it was confirmed that the unreacted
precursor compound 8 was able to be removed to less than a detection limit value.
In case where a toluene sulfonic acid ester group is used as a leaving group, instead
of the sulfonic acid ester group having an alkyl amide tag introduced according to
the present invention, a mixed amount of the unreacted precursor compound was 115
µg/mL. Thus, it was confirmed that an aldosterone synthase imaging agent low in contamination
of the unreacted precursor compound was able to be synthesized by the present invention
even without the HPLC purification.
HPLC condition
[0078]
Column: XBridge Phenyl (trade name, manufactured by Nippon Waters K.K., particle size:
3.5 µm, size: 4.6 mmϕ x 100 mm)
Mobile phase: 10 mmol/L ammonium carbonate solution/methanol = 50/50 → 35/65 (0 →
10 minutes), 35/65 → 0/100 (10 → 25 minutes), 0/100 (25 → 50 minutes)
Flow rate: 1.0 mL/min
Detector: ultraviolet-visible absorption photometer (detection wavelength: 254 nm)
[0079] This application claims priority based on Japanese Patent Application No.
2017-042783 filed on March 7, 2017, the disclosure of which is incorporated herein in its entirety.